Hepatic microsomal cytochromes P-450 of rats treated with phenobarbital metabolized chloramphenicol (CAP) aerobicaly to p-nitrobenzyl alcohol, N-(2-oxoethyl) -dichloroacetamide, N-(2-hydroxyethyl)-dichloroacetamide, and CAP aldehyd (CAP with the primary alcohol group oxidized to an aldehyde group). The first step in the formation of these products is the oxidation of CAP to CAP aldehyde. This Beta-hydroxyaldehyde can undergo either spontaneously or catalytically a retro-aldo-scission to p-nitrobenzaldehyde and N-(2-oxoethyl) dichloroacetamide. These intermediates are rapidly reduced by a NADPH or NADH dependent reductase to p-nitrobenzyl alcohol and N-(2 hydroxyethyl)-dichloro-acetamide respectively. Under conditions of low oxygen tension, cytochromes P-450 catalyzes a reductive dechlorination of CAP into a monochloro-radical intermediate. This reactive species can either abstract a hydgrogen atom from the medium to yield deschloro-CAP or react covalently with microsomal protein. Since cytochrome P-450 is destroyed during this sequence of reactions it is possible that it is a major site of covalent interaction. The destruction of cytochrome P-450 may explain how CAP alters the metabolism and toxicity of a variety of compounds.